Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
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Activation of Extracellular-Signal Regulated Kinase by Platelet-Derived Growth Factor Is Potentiated by Phenylephrine in Primary Cultures of Adult Rat Hepatocytes
Hajime MotekiMitsutoshi KimuraMasahiko Ogihara
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2011 年 34 巻 7 号 p. 980-986

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We investigated the effects of the α1-adrenergic agonist phenylephrine on platelet-derived growth factor (PDGF)-stimulated extracellular signal-regulated kinase (ERK) in primary cultures of adult rat hepatocytes. Hepatocytes were isolated and cultured with PDGF (10 ng/ml) and/or α-adrenergic agonist. Phosphorylated ERK isoforms (ERK1 and ERK2) were detected by Western blotting analysis using anti-phospho mitogen-activated protein kinase (MAPK) antibody. PDGF stimulated phosphorylation of ERK2 (42 kDa MAPK) by 2.0-fold within 3—5 min. The PDGF-induced ERK activation was abolished by AG1296 (10−7 M) or LY294002 (10−7 M) treatment. MAPK kinase inhibitor, PD98059 (10−6 M), completely inhibited the PDGF-induced increase in ERK activity. In addition, PDGF-induced mammalian target of rapamycin activity was completely inhibited by AG1296, LY294002, PD98059, or rapamycin treatment. Phenylephrine alone showed no effects on ERKs, but significantly increased phosphorylation of ERK2 induced by PDGF. Moreover, a synthetic analog of diacylglycerol (DG), phorbol 12-myristate 13 acetate (TPA; 10−7 M), potentiated PDGF-induced ERK2 phosphorylation, while ionomycin had no effect (10−6 M). The effects of phenylephrine and TPA were antagonized by the phospholipase C (PLC) inhibitor U73122 (10−7 M), and the protein kinase C (PKC) inhibitor GF109203X (10−7 M), respectively. Accordingly, PDGF-induced DNA synthesis and proliferation in the presence or absence of phenylephrine or TPA were completely inhibited by AG1296, LY294002, PD98059, or rapamycin treatment. These results suggest that activation of PLC/PKC by phenylephrine represent an indirect positive regulatory mechanism for stimulating ERK induced by 10 ng/ml PDGF.

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© 2011 The Pharmaceutical Society of Japan
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